Viruses are known to play an important role in many lymphoproliferative diseases in animal models. The role of viruses as pathogenetic agents in human malignant lymphoma and leukemia is less clear. Epstein-Barr virus (EBV) plays an important role in some human cancers such as Burkitt's lymhoma and nasopharyngeal carcinoma. Recently, EBV has been identified as a possible co-factor in other diseases, such as Hodgkin's disease, lymphomatoid granulomatosis, nasal angiocentric T/NK cell lymphoma, HIV-associated lymphoma, and post-transplant lymphoproliferative disease of both B and T cell derivation. We are studying the expression of EBV-associated genes in human lymphoproliferative disease, and exploring the role of gene deletion and/or mutation in pathogenesis. We are also studying the role of gene expression in the pathophysiology of EBV-associated lymphoproliferative disease. We have identifed a profile of EBV-induced chemokines which appear to be involved in the pathogenesis of EBV-associated tissue necrosis. This work also has led to the development of novel therapeutic approaches for EBV-associated lymphoproliferative disease, such as immunotherapy utilizing both immunotoxins and immunomodulators. We are also exploring the role of other viral agents in the pathogenesis of human malignant lymphoma and leukemia. These include HHV-8/KSHV which is usually found in association with EBV, and appears to be linked to a unique form of immunodeficiency associated lymphoma. Finally, we are continuing to investigate the role of human retroviruses, such as HTLV-I/II in the pathogenesis of T-cell malignancies.